Bone Quality PART 1 Introduction Architecture Turnover Old

Bone Quality PART 1 Introduction Architecture Turnover

Old Definition of Osteoporosis A systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Conference Report from the Consensus Development Conference: Am J Med 94: 646 -650, 1993

Relationship Between BMD and Fracture • Low baseline bone mineral density (BMD) predicts increased risk of subsequent fractures • The magnitude of the increases in BMD with antiresorptive therapies differs greatly, yet the vertebral fracture risk reductions are similar • There is only a weak relationship between changes in BMD with antiresorptive therapy and the reduction in risk of new fractures

What May Contribute to an Increase in BMD? • Increased mineralization in existing bone • Increased bone tissue per unit of bone volume: • Filling in resorption space • Widening existing trabeculae • Creating new trabeculae • Increased bone size

Age and Bone Mass as Predictors of Fracture Age (Years) Fracture Risk / 1000 Person Year 160 80+ 140 120 75 -79 100 80 70 -74 60 65 -69 60 -64 55 -59 40 50 -54 45 -49 <45 20 0 >1. 0 0. 90 -0. 99 0. 80 -0. 89 0. 70 -0. 79 0. 60 -0. 69 Forearm Bone Mass (g/cm 2) Hui SL et al. J Clin Invest 81: 1804 -1809; 1988 <0. 60

BMD Change and Fracture Risk Reduction with Antiresorptive Therapy • Fracture Risk decreases by 6 -12 months, before maximum BMD response has occurred • Treatment may reduce fracture risk with little or no change in BMD • From regression analyses, only a small proportion of fracture risk reduction is attributable to an increase in BMD

Vertebral Fracture Risk Reduction Attributable to an Increase in BMD Antiresorptive Therapy Risedronate 1 7 – 28% Alendronate 2 16% Raloxifene 3 4% 1. Li et al. Stat Med 20: 3175 -88; 2001 2. Cummings et al. Am J Med 112: 281 -289; 2002 3. Sarkar et al. J Bone Miner Res 17: 1 -10; 2002

Randomized Studies of Antiresorptives in Postmenopausal Osteoporotic Women* Risk of Vertebral Fractures LS BMD** Raloxifene 60 mg/d Preexisting vertebral fracture (VFx)1 No preexisting VFx 1 2. 2 Alendronate 5/10 mg/d Preexisting VFx 2 No preexisting VFx 3 6. 2 6. 8 Risedronate 5 mg/d Preexisting VFx 4 No preexisting VFx 5 4. 3 5. 9 Calcitonin 200 IU/d Preexisting VFx 6 0. 7 2. 9 0 *Not head -to-head comparison, **vs placebo 1 Data on file, Eli Lilly & Co. 2 Black DM et al. Lancet 348: 1535 -1541, 1996 3 Cummings SR et al. JAMA 280: 2077 -2082, 1998 Relative Risk (95% CI) 4 Harris 0. 5 1. 0 ST et al. JAMA 282: 1344 -1352, 1999 JY et al. Osteoporosis Int 11: 83 -91, 2000 6 Chesnut CH et al. Am J Med 109: 267 -276, 2000 5 Reginster

Relationship Between Baseline Femoral Neck BMD and Vertebral Fracture Risk % Risk of 1 New Vertebral Fracture at 3 Years MORE Trial - 3 Years 22 20 Raloxifene (pooled) 18 Placebo 16 14 95% Confidence Interval 12 10 8 6 4 2 0 -3. 2 -2. 8 -2. 6 -2. 4 -2. 2 -2. 0 -1. 8 -1. 6 Baseline Femoral Neck BMD T-Score (NHANES) Adapted from Sarkar S et al. J Bone Miner Res 17: 1 -10, 2002

Relationship Between Change in Femoral Neck BMD and Vertebral Fracture Risk MORE Trial - 3 Years Raloxifene (pooled) 15 Placebo 95% confidence interval % Risk of 1 New Vertebral Fracture 13 11 9 7 5 3 0 -10 -8 -6 -4 -2 0 2 4 6 8 10 % Change in Femoral Neck BMD Adapted from: Sarkar S et al. J Bone Miner Res 17: 1 -10, 2002

Relationship Between Change in Femoral Neck BMD and Vertebral Fracture Risk of 1 New Vertebral Fracture at 3 Years (%) MORE Trial – 3 Years 15 13 Raloxifene (pooled) Placebo 11 9 7 A B 5 3 B A 0 -10 -8 -6 -4 -2 0 2 4 6 8 10 % Change in Femoral Neck BMD at 3 Years Adapted from Sarkar S et al. J Bone Miner Res 17: 1 -10, 2002

Many Characteristics of Bone Strength Are Not Reflected in DXA Results • Reflected in DXA Measurements: • Bone size • Trabecular volume and cortical thickness • Amount of mineralization in bone and surrounding tissues • Not Reflected in DXA Measurements: • Trabecular connectivity and number • Collagen quality • Microscopic damage (e. g. microcracks) • Bone geometry

Current Definition of Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality. Normal bone Osteoporosis NIH Consensus Development Panel on Osteoporosis JAMA 285: 785 -95; 2001

Shifting the Osteoporosis Paradigm Bone Strength NIH Consensus Statement 2000 Bone Strength Bone Quality and Bone Mineral Density Architecture Turnover rate Damage Accumulation Degree of Mineralization Properties of the collagen/mineral matrix Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 285: 785 -95; 2001

Components of Bone Quality • Architecture • Macroarchitecture (bone geometry) • Microarchitecture (trabecular connectivity and shape) • Bone turnover • Resorption • Formation • Material properties • Collagen properties (cross-linking) • Mineralization (degree and heterogeneity) • Microdamage (microcracks) Chesnut III CH. J Bone Miner Res 16: 2163 -2172, 2001 NIH Consensus Development Panel on Osteoporosis. JAMA 285: 785 -95; 2001

Bone Quality Architecture Turnover Rate Damage Accumulation Degree of Mineralization Properties of the collagen/mineral matrix Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 285: 785 -95; 2001

Distribution of Cortical and Trabecular Bone Thoracic and Lumbar Spine 75% trabecular 25% cortical 1/3 Radius >95% Cortical Femoral Neck 25% trabecular 75% cortical Hip Intertrochanteric Region 50% trabecular 50% cortical Ultradistal Radius 25% trabecular 75% cortical

Cortical and Trabecular Bone Cortical Bone • 80% of all the bone in the body • 20% of bone turnover Trabecular Bone • 20% of all bone in the body • 80% of bone turnover

Relevance of Architecture Normal Quantity and Architecture Loss of Quantity and Architecture

Bone Architecture Trabecular Perforation The effects of bone turnover on the structural role of trabeculae Risk of Trabecular Perforation increases with: • Increased bone turnover • Increased erosion depth • Predisposition to trabecular thinning

Structural Role of Trabeculae Compressive strength of connected and disconnected trabeculae 1 Bell et al. Calcified Tissue Research 1: 75 -86, 1967 16 X

Resorption Cavities as Mechanical Stress Risers Normal Osteoporotic Adapted from Parfitt A. M. et al. Am J Med 91, Suppl 5 B: 5 B-34 S

Strain Distribution in Relation to Trabecular Perforations • Trabeculae under low strain (blue) can tolerate bone loss better than traceculae under high strain (red) • Resorption of trabeculae causes a larger decrease in stiffness than does thinning of trabeculae Reprinted with Permission from Van der Linden et al. J Bone Miner Res 16: 457 -465; 2001

Trabecular Perforations Reprinted with Permission from Mosekilde L. Bone Miner 10: 13 -35, 1990 Seeman Lancet 359, 1841 -1850, 2002.

Antiresorptive Agents Help to Preserve Supporting Ties Reprinted with Permission from Mosekilde L. Bone 9: 247 -250, 1988

Bone Architecture Cortical Bone Fracture Risk Increases With: • Increased Bone turnover • Decreased cortical thickness • Changes in dimensions

Effects of Antiresorptive Drugs High turnover state: endosteal resorption and increased porosity Stress Risers Fracture at a Stress Riser Low turnover state: reduced endosteal resorption and porosity

Effect of Teriparatide [rh PTH(1 -34)] on Radial BMD • Periosteal apposition of new bone that is not yet fully mineralized • Endosteal resorption of normal or highly mineralized bone BMD Zanchetta JR et al. JBMR 18, 539 -534, 2003

Possible Mechanism for Reduced BMD Response to TPTD Among Alendronate-Pretreated Patients Pretreatment After Alendronate TPTD Treatment BMD bone mass mineralization remodeling space porosity 1 1 Boivin, Bone 2000, 2 Burr, JBMR 2001, 3 Zanchetta, IOF 2001 endosteal porosity 2 periosteal new bone cortical area 3

Teriparatide - Effect on Cortical Bone Improves geometry-Increases diameter Increases thickness

FACT Trial Percent change at 6 months Lumbar Spine BMD Areal (DXA) and Volumetric (QCT) † QCT Subset * Jiang UCSF † TPTD (n = 16) ALN (n = 19) * Mc. Clung et al. Osteoporos Int. 2002 * Within treatment: *P<0. 01 Treatment difference: †P<0. 01

Teriparatide Effects on the Femoral Midshaft of Ovariectomized Monkeys Sham Ovx Data on file, Eli Lilly PTH 1 W PTH 5 W

Effect of 20 g Teriparatide on Trabecular and Cortical Architecture Baseline Eriksen et al ACR 2002 Follow-up

3 -D Structural Indices in Women in the Teriparatide Fracture Prevention Trial Quantitative analysis-Significant changes Trabecular bone volume P<0. 001 Structure model index P<0. 025 Connectivity density P<0. 034 Cortical thickness P<0. 012 Eriksen et al ACR 2002

Effect of 20 g Teriparatide on Bone Histology -Iliac crest bone biopsies • Increased trabecular bone volume • Shifted trabeculae toward a more plate-like structure • Increased trabecular bone connectivity • Increased cortical bone thickness with no increase in cortical porosity Eriksen et al ACR 2002

Bone Quality Architecture Turnover Rate Damage Accumulation Degree of Mineralization Properties of the collagen/mineral matrix Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 285: 785 -95; 2001

Bone Remodeling Process Osteoclasts Lining Cells Resorption Cavities Bone Lining Cells Mineralized Bone Osteoblasts Osteoid

High Bone Turnover Leads to Development of Stress Risers and Perforations Osteoclasts Lining Cells Bone Perforations Stress Risers

Consequences of an Imbalance in Bone Turnover Normal Bone Osteoporotic Bone Mechanism of Action Animation of Bone Remodeling Process, 2002, Eli Lilly

Bone Turnover, Mineralization, and Bone Quality • There is a complex relationship between bone turnover and bone quality • A decrease of bone turnover increases mineralization and permits filling of remodeling space Excessive suppression Increased mineralization Accumulation of microcracks Increased brittleness Skeletal fragility

Antiresorptive Agents Increase BMD by Decreasing Remodeling Space and/or Prolonging Mineralization Antiresorptive Agent Remodeling space Newly formed bone Increased Mineralization

Rate of Bone Turnover Clinical paradigm: Bone turnover is an essential physiological mechanism for repairing microdamage and replacing “old” bone by “new” bone Clinical question: Can excessive reduction in bone turnover be harmful for bone? How much suppression is too much?

Changes in Biochemical Markers Predict an Increase in Bone Mineral Density During Antiresorptive Therapy • Treatment with antiresorptive agents produce greater proportional changes in bone turnover markers than in BMD • Measurable changes in bone turnover markers tend to occur before changes in BMD • There are significant correlations between changes in bone turnover markers and changes in BMD Adapted from Looker AC et al. Osteoporos Int 11: 467 -480; 2000

Bone Turnover Markers • Bone turnover markers are components of bone matrix or enzymes that are released from cells or matrix during the process of bone remodeling (resorption and formation). • Bone turnover markers reflect but do not regulate bone remodeling dynamics.

Urinary Markers of Bone Resorption Marker Abbreviation Hydroxyproline HYP Pyridinoline PYD Deoxypyridinoline DPD N-terminal cross-linking telopeptide of type I collagen NTX C-terminal cross-linking telopeptide of type I collagen CTX Delmas PD. J Bone Miner Res 16: 2370; 2001

Serum Markers of Bone Turnover Abbreviation Formation Bone alkaline phosphatase ALP (BSAP) Osteocalcin OC Procollagen type I C-propeptide PICP Procollagen type I N-propeptide PINP Resorption N-terminal cross-linking telopeptide of type I collagen NTX C-terminal cross-linking telopeptide of type I collagen CTX Tartrate-resistant acid phosphatase TRAP Delmas PD. J Bone Miner Res 16: 2370, 2001

Relationship Between Changes in Bone Resorption Markers and Vertebral Fracture Risk VERT Study • A decrease in urinary CTX and NTX at 3 -6 months was associated with vertebral fracture risk at 3 years • A decrease in urinary CTX >60% and of urinary NTX >40% gave little added benefit in fracture reduction Adapted from Eastell R et al. Osteoporos Int 13: 520; 2002

Raloxifene and Alendronate Reduce Bone Turnover in Women with Osteoporosis Mean Serum PINP ( g/L) 500 50 40 300 Premenopausal 200 * Mean ± SD Mean Serum CTX (ng/L) 30 10 0 0 ALN * 20 100 RLX Premenopausal ALN RLX *p< 0. 01 compared to premenopausal levels Adapted from Stepan JJ et al. J Bone Miner Res 17 (Suppl 1): S 233; 2002

Bone Turnover Effects Bone Quality • Very low turnover leads to excessive mineralization and the accumulation of microdamage • Very high turnover leads to accumulation of perforations and a negative bone balance